New Synthesis-Enabling Reactions and Reaction Cascades for the Discovery and Production of Potential Anti-Cancer Compounds

除了外科手术刀和放射治疗外，化疗是最有效的武器之一，特别是对于不可手术和侵袭性癌症，如小细胞肺癌。迄今为止，癌症仍然比有效药物多得多，仍然需要选择性和有效的有效抗癌治疗。临床上使用的大多数现有药物是天然来源的或这些天然产物的人造类似物。这些（通常）具有细胞毒性的天然产物被宿主生物体用作自卫手段，数千年来，它们在对抗捕食者的行动模式中已经进化得既有效又有选择性。一个很好的例子是紫杉醇（paclitaxel），它最初是从太平洋紫杉树中分离出来的，目前用于治疗肺癌、卵巢癌和乳腺癌。如果天然产物可以大规模和可持续的方式收获，或者在实验室中通过发酵技术创造，那么就可以开发出有效的可销售药物。如果这是不可能的，唯一剩下的选择是通过化学合成过程制造。然而，这些目标分子通常具有如此复杂的三维结构，使得传统的一步一锅化学合成方法变得如此冗长，以至于只能获得毫克量。这个问题可以通过战略性地实施新的合成，使反应和反应级联从合适的和容易获得的起始材料进入化学路线来克服。这些可以允许在大约15个步骤中构建复杂的靶分子，而使用传统方法则需要30-40个步骤。在大约15个步骤中合成复杂分子意味着这些分子（和类似物库）现在可以快速制造，并且可能在克级上制造。此外，可以获得大量部分类似于天然产物的后期中间体，并将其转化为结构简化的天然产物类似物的文库。这样的合成能力可以允许第一次进行彻底的生物学评价，并产生强大的结构/活性关系，这些关系可以反馈到合成循环中，潜在地导致具有增强的生物活性的化合物，并最终导致有吸引力的候选药物。在过去的3年里，我们的团队一直致力于发现和开发新的不对称催化剂，新的强大的催化剂使能的合成方法，以及与此提议最相关的新催化剂和多催化剂使能的反应级联序列。反应级联在合成中是强大的，因为它们允许在单个容器中发生一系列成键反应，从而构建复杂性并最大化效率。通过明智地选择起始材料和催化剂，可以在一个有效的操作中产生高级中间体。在五年的奖学金期间，我们希望显着扩大这些初步研究所开辟的研究领域，开发新的催化剂使合成方法和反应级联，并将研究结果应用于一些复杂的生物活性生物碱天然产物的全合成。对于奖学金的前三年，我们希望开发新的化学和战略，导致短和有效的立体选择性全合成daphniyunnine D和manzamine A（及其类似物的生物评价和SAR的发展）。

Alongside the surgeon's knife and radiotherapy, chemotherapy is one of the most effective weapons especially on inoperable and aggressive cancers such as small cell lung cancer. To date there are still many more cancers than effective medicines and there remains the need for effective anti-cancer treatments that are both selective and potent. The majority of the existing drugs in clinical use are of natural origin or are man made analogues of these natural products. These (often) cytotoxic natural products are employed by the host organism as a means of self-defense and over millennia have evolved to be both potent and selective in their modes of action against predators. An excellent example is paclitaxel [taxol] first isolated from the pacific yew tree and currently used in the treatment of lung, ovarian and breast cancers. If the natural product can be harvested on scale and in a sustainable fashion, or be created by fermentation techniques in the laboratory, then an effective marketable drug can be developed. When this is not possible the only remaining option is to manufacture through the process of chemical synthesis. However, these target molecules often possess such complex three dimensional structures that the traditional, one-step, one-pot chemical synthesis approaches become so lengthy that only milligram quantities can be obtained. This problem maybe overcome by the strategic implementation of new synthesis enabling reactions and reaction cascades into chemical routes from appropriate and readily available starting materials. These can allow the construction of the complex target molecules in around 15 steps, compared with 30-40 steps using traditional approaches. Accessing complex molecules in around 15 steps means that these molecules (and libraries of analogues) may now be made at speed and possibly on gram scale. In addition, large quantities of late stage intermediates resembling in part the natural product can be accessed and converted into libraries of structurally simplified natural product analogues. Such synthesis capability may allow thorough biological evaluation for the first time and the creation of powerful structure / activity relationships that can be fed back into the synthesis cycle, potentially resulting in compounds with enhanced biological activity, and eventually lead to attractive drug candidates. Our group has been engaged over the past 3 years in the discovery and development of new asymmetric catalysts, new powerful catalyst-enabled synthetic methodology and most relevant to this proposal, new catalyst and multi-catalyst enabled reaction cascade sequences. Reaction cascades are powerful in synthesis as they allow a series of bond-forming reactions to occur in a single vessel / thus building complexity and maximizing efficiency. By judicious choice of starting materials and catalysts, advanced intermediates can be created in one efficient operation. During the five year Fellowship we wish to significantly expand the lines of research opened up by these preliminary studies, develop new catalyst enabled synthetic methodology and reaction cascades, and apply the findings to the total synthesis of a number of complex bioactive alkaloid natural products. For the first three years of the fellowship we wish to develop new chemistry and strategies leading to the short and effective stereoselective total synthesis of both daphniyunnine D and manzamine A (and their analogues for biological evaluation and the development of SAR).